Corticosteroids and Fetal Intervention Interact to Alter Lung Maturation in Preterm Lambs

Abstract

MATERIALS AND METHODSincrease lung volumes, and decrease epithelial and endothelial permeability without increasing alveolar surfactant pool sizes in ventilated preterm rabbits and sheep (4,5). Prenatal corticosteroid exposure also can alter neuroendocrine adaptation and increase blood pressure and cardiac performance in the preterm resulting indirectly in improvements in pulmonary performance (6). Despite these many observations. inconsistent responses to prenatal corticosteroid exposure continue to be reported. For example. Liggins' group found a modest increase in pressurevolume curves of preterm lambs in one study but no effect in a second study (7,8). These disparate results may reflect the difficulty of manipulating a fetus without inadvertently influencing lung maturation (9). In fetal sheep, the manipulation is generally the placement of fetal catheters for delivery of agents to be tested for maturational responses. Moreover, prenatal exposure to corticosteroids is efficacious in only about 50% of human fetuses at risk for preterm delivery (3). We thought that a fetus may need to be primed by prior adverse pregnancy events to consistently respond to corticosteroids. Our hypothesis was that the timing of surgery to place the fetal infusion catheter would alter the fetal milieu and thus alter the fetal response.Experimental design. Pregnant Western mixed-breed ewes with twin pregnancies were divided into two groups based on the time of surgery. Fetal catheterization was performed in the early surgery group at 117 ± I d gestational age and at 122 ± I d gestational age in the late surgery group. Cortisol infusions or the control saline infusions were begun on d 126, with delivery 60 h later on d 128. The animals catheterized at 122 d were reported in a concurrent investigation of combination hormonal and surfactant therapy on preterm lung function (4). The gestational age of 128 d was selected to correspond with that used by Liggins' group (7,8) and by other investigators studying fetal lung maturation (10).Fetal catheterization. Guidelines for the care and use of animals approved by our institutional review board were followed during the experiment. On the day of surgery. each ewe was anesthetized with 1.2 mg of atropine and 700 mg of ketamine given by intramuscular injection, followed by a continuous intravascular infusion of ketamine at 100 mg/h (4). Through a midline abdominal incision. a single fetal hind limb was exposed via a small hysterotomy. With use of local field block with lidocaine, the dorsal hind limb artery and vein were catheterized with polyethylene tubing to the level of the abdominal aorta and inferior vena cava, respectively. The fetal wound and hysterotomy were then closed and the procedure repeated on the second twin. Before closing the abdominal incision. the catheters were exteriorized to the maternal flank. The catheters were then filled with 1000 U/mL heparin, capped, and secured in a cloth pouch on the ewe's flank. The catheters were flushed daily to maintain The 117-d cortisol-i...

Prenatal Dexamethasone and Exogenous Surfactant Therapy: Surface Activity and Surfactant Components in Airway Specimens

“…In studies using human fetal lung explant, glucocortic oids have both a stimulatory and an inhibitory effect on the SP-A synthesis: low doses and short exposure stimulate, whereas high doses and long exposure inhibit the synthesis of SP-A (7). Furthermore, prenatal glucocorticoid treatment increases the expression of SP-A in the whole lung of the rat fetus (26), and prenatal glucocorticoid treatment combined with TSH-releasing hormone or fetal intervention s increases the alveolar pool size of SP-A in ventilated preterm sheep (12,27). In the present study, prenatal glucocorticoid administration tended to increase the ratio between SP-A and PC on the first day of life.…”

Effects of Antenatal Corticosteroids on Regional Brain and Non-neural Tissue Water Content in the Ovine Fetus

“…29 Antenatal dexamethasone treatment of the ewes resulted in 2.2% to 6.8% reductions in regional brain water content at 60% of gestation ( Figure 3) compared with maturational changes in regional brain water content, which ranged from 20% to 46% (Figure 1). 19 Treatment of the ewes with corticosteroids did not have major effects on the brain or plasma electrolyte homeostasis of the fetuses. Moreover, catheterization of the fetus was also associated with 3.5-7.4% reductions in regional brain water content at 60% of gestation ( Table 3), suggesting that the stress of fetal surgery at this age also results in decreases in regional brain water that are as large as those observed after than matemal antenatal corticosteroid treatment.…”

“…1 5 Previous studies have shown that the response of the fetal lung to a maturational agent such as cortisol depends on the history of previous fetal interventions. 19 When a twin pregnancy was present, we initially obtained tissue samples from both the catheterized and noncatheterized fetuses. However, because catheterization represents a major fetal stressor, we analyzed the effects of catheterization on regional fetal water content and found that it was lower in the catheterized than the noncatheterized fetuses of the placebo-treated ewes (Table 3).…”

Effects of Antenatal Colonization with Ureaplasma urealyticum on Pulmonary Disease in the Immature Baboon

“…That we did not expose control animals to a sham amniocentesis 48 h before delivery also leaves open the possibility that procedure-related stress may have contributed in a beneficial way to those infants who subsequently cleared the Ureaplasma from their airways (53).…”